Allergic rhinitis, which can be seasonal (hay fever) or perennial, is an upper-airway disorder that typically results in sneezing, nasal irritation, rhinorrhea and nasal congestion.
Asthma, which affects approximately 10% of the population, is a disorder that results in obstruction of the airways, bronchial hypereactivity and airway inflammation. The primary symptoms of asthma are coughing, wheezing, dyspnoea and tightening of the chest.
Local allergen challenge in sensitised individuals prompts an allergic and immune response, of which mast cells are known to play a central role. Mast cells become activated on challenge with IgE dependent stimuli, resulting in the release of chemical mediators. Various mast cell mediators, such as histamine, prostaglandin D2 (PGD2), leukotrienes and cytokines, have been implicated in the pathogenesis of allergic disorders.
Prostaglandins are produced by mast cells through the metabolism of arachidonic acid by cyclo-oxygenase (COX). Prostagladin D2 (PGD2) is the major cyclooxygenase derived metabolite produced on immunological challenge (Lewis R A, Soter N A, Diamond P T, Austen K F, Oates J A, Roberts L J II, J Immunol. 129, 1627-1631, 1982). It has been demonstrated that PGD2 concentration in sensitised individuals increases in the presence of an allergen. In asthmatics, a bronchiol allergen challenge leads to a rapid rise in PGD2 levels in the bronchoalveolar lavage (BAL) fluid [Murray J J et al, N. Engl. J. Med. 315, 800-804 (1986)]. Additionally, in individuals with allergic rhinitis and atopic dermatitis, antigen challenge causes a rise in PDG2 levels in the nasal mucosa and skin, respectively (Naclerio R M et al, AM. Rev. Respir. Dis. 128, 597-602 (1983); and Charlesworth E N, J. Immunol. 146, 671-676 (1991)).
Intravenous administration of PGD2 results in intense facial flushing and nasal congestion (Heavey D J et al, 28, 755-767 (1984)). PGD2 is thought to induce nasal congestion in individuals with allergic rhinitis by causing vasodilation in the nasal mucosa (Park Y J, Clin. Allergy Immunol. 2002, 16, 275-293). It has been shown that insufflation of PGD2 in humans results in a dose-dependent increase in nasal congestion.
PGD2 exerts its activity through interaction with two distinct G-Protein-linked receptors: the D-prostanoid receptor 1 (DP1) and the chemoattractant receptor homologous-molecule expressed on TH2 cells (CRTH2).
Allergic and immune responses in patients with allergic disorders are complex. Research has demonstrated that mediators, such as PGD2, are responsible for the antigen-induced responses.
Antagonists of the DP1 receptor may also be useful in the treatment of niacin induced flushing. Niacin, also referred to as nicotinic acid, is a water soluble vitamin that is used in the treatment of hypercholesterolaemia. Niacin reduces levels of low density lipoprotein cholesterol (LDL-C), as well as triglycerides (TG), whilst elevating the levels of high density lipoprotein cholesterol (HDL-C), thereby reducing cardiovascular morbidity and mortality. The most common side effect associated with niacin treatment is flushing, caused by its vasodilatory properties. Antagonism of the DP1 receptor has been shown to limit or prevent niacin induced flushing.
There is a need for therapeutic agents which act as DP1 receptor antagonists. Disclosed herein are bicyclic imidazole compounds that represent a novel class of DP1 receptor antagonists.